Title: Control of Excitatory Synapse Formation by Huntingtin Abstract: Huntington?s Disease (HD) is an inherited, fatal neurodegenerative disease caused by an expansion of poly-glutamine (poly-Q) repeats in the N-terminus of the Huntingtin (Htt) protein. While the causative mutation for HD can be detected long before disease onset, there are currently no treatments to prevent or delay neurodegeneration in HD. The dominant nature of the Htt mutation led to the hypothesis that HD is caused by a toxic gain-of-function of the mutant Htt protein. Therefore, the majority of HD therapeutic strategies are focused on reducing or eliminating mutant Htt. Recent work from our laboratory and others suggests an alternative hypothesis, that loss of Htt function is also a major driver of disease pathogenesis. In mouse genetic studies, our lab found that cortical Htt is required for the correct establishment of cortical and cortico- striatal excitatory synaptic connections, and that this function of Htt is lost when mutant Htt is present. What are the functions of wild-type Htt in establishing and maintaining synaptic connections? How does disruption of wild-type Htt function contribute to HD pathogenesis? These are the questions that I will answer during my postdoctoral research in Dr. Cagla Eroglu?s laboratory at Duke University. In my preliminary experiments I found an unexpected role for neuronal Htt as a regulator of astrocyte- induced synaptogenesis. Astrocytes secrete thrombospondin (TSP) family proteins, which induce synapse formation via their neuronal receptor, the gabapentin receptor ?2?-1. In biochemical experiments, I found that ?2?-1 directly interacts with wildtype Htt, but this interaction is impaired when the disease-causing poly-Q repeat expansion is present in Htt. Furthermore, Htt is required in neurons to suppress synaptogenesis in the absence of TSP signaling, suggesting that Htt and ?2?-1 have opposing functions that balance the growth of excitatory synaptic connectivity. Based on these findings, I developed the hypothesis that Htt is an inhibitor of excitatory synapse formation. I will use a combination of primary neuronal culture, molecular biology, biochemistry, confocal microscopy, and mouse genetics, to test the hypothesis that Htt controls synaptic connectivity through its interaction with ?2?-1, and that this function of Htt is impaired when the poly-Q expansion is present. Additionally, I will determine whether the genetic manipulation of ?2?-1 expression can rescue synaptic deficits and delay or stop disease progression in HD model mice. Collectively, I expect these studies will significantly advance the field of HD research by identifying specific molecular mechanisms through which loss of wild-type Htt function contributes to disease pathogenesis. Furthermore, these findings are poised to provide novel therapeutic strategies to treat early synaptic dysfunction and delay or prevent onset of neurodegeneration in HD.